The long-term objective of this project is to develop validated, genetic biomarkers to aid in more accurate diagnosis and targeted treatment of schizophrenia and related neuropsychiatric illnesses, including bipolar disorder. In Phase I, SureGene demonstrated the feasibility of using specific dimensions of mental illness to discover novel genes and genetic variants that influence risk and impact the clinical presentation of these diseases. This project will build on first-generation genetic biomarkers in the form of single nucleotide polymorphisms (SNPs) and chromosomally-related associations of these polymorphisms called haplotypes. The Phase II project will further develop biomarkers for neuropsychiatric illnesses using a set of genes that meet stringent criteria for genetic replication. The project will develop products for research and clinical applications that combine biomarkers in these genes. The aims are 1) Develop a prototype AssureGeneTM array and data set for schizophrenia-spectrum disorders. SureGene will develop a flexible SNP genotyping product incorporating a high density of SNPs in approximately 200 genes and generate a detailed data set relating genotypes to phenotypes based on 2000 NIMH schizophrenia, bipolar, and control samples. A first-generation array and data set will be made available to the research community by the middle of Grant Year 2. A refined array and data set for prospective clinical applications will be completed by the end of Phase II. 2) Evaluate the utility of the AssureGeneTM test for differential diagnosis and for predicting progression to clinically defined psychosis. SureGene will develop genetic algorithms for the array for use in predicting dichotomous clinical outcomes. This Aim should provide a collective set of predictive models that can be evaluated on the basis of their sensitivity, specificity, and overall classification accuracy. 3) Develop and implement a flexible medical resequencing platform (ExonReadTM) for high priority genes. SureGene will develop a cost-effective "next generation" medical resequencing platform that can be used by the research community to evaluate the contribution of rare or spontaneous mutations in key genes contributing to psychopathology and clinical outcomes for neuropsychiatric illnesses. A prototype sequencing platform for research use will be completed in Grant Year 2. SureGene will apply ExonReadTM to a sample of African Americans and Caucasians with a family history of schizophrenia or bipolar disorder to establish baseline expectations and limitations of the product. The commercial potential for these products is significant. By targeting common variants, the AssureGeneTM array should have broad applicability in research and clinical settings, with both diagnostic and pharmacogenetic applications. The ExonReadTM platform will be a valuable, cost-effective tool for identifying rare or unique high penetrance mutations expected in familial cases of neuropsychiatric illnesses and will have applications for genetic counseling and for differential diagnosis. PUBLIC HEALTH RELEVANCE: The long term objective of this project is to develop validated gene-related tests (genetic biomarkers) to aid in more accurate diagnosis and customized treatment of schizophrenia and related "schizophrenia spectrum" disorders, including bipolar disorder. SureGene's goals for this research are to refine existing genetic biomarkers and to discover and refine additional novel genetic biomarkers. Products based on these biomarkers should be helpful to individuals suffering from schizophrenia and related disorders, their families and health care providers, and researchers seeking to improve diagnosis and treatment.